Type II transmembrane serine proteases are a family of proteases characterized by an N-terminal transmembrane domain (Bugge et al., J. Biol. Chem. 284 (35): 23177-23181, 2009; Hooper et al., J. Biol. Chem. 272(2): 857-860, 2001). All members of this family are expressed as single-chain zymogens and are proteolytically activated by cleavage within a highly conserved R/(IV)VGG motif. One member of the family, transmembrane protease, serine type 4 (TMPRSS4), has been shown to activate the epithelial sodium channel (ENaC) regulating the sodium and water flux across epithelia (Guipponi et al. 2002 Hum. Mol. Genet. 11:2829; Vuagniaux et al. 2002 J. Gen. Physiol. 120:191). The proteolytical activators of TMPRSS4 are unknown; however, data available to date suggests that the protein is autoactivated. When activated, the catalytic domain of TMPRSS4 remains bound to the N-terminus of the protein via a disulphide linkage. TMPRSS4, TMPRSS2 and TMPRSS11D (or Human Airway Trypsin-like protease; “HAT”) have been shown in vitro to cleave influenza A hemagglutinin (HA), which is the first essential step in the viral life cycle. This cleavage is essential for activity of HA, as the protein is synthesized as a precursor protein (HA0) and requires cleavage into HA1 and HA2 for activity. RNAi knock-down of TMPRSS4 in Caco-2 cells resulted in reduced spread of the virus. In addition, TMPRSS4 was shown to be strongly upregulated in the lungs of mice infected with influenza (Böttcher et al. 2006 J. Virol. 80:9896; Böttcher et al. 2009 Vaccine 27: 6324; Böttcher-Friebershäusser et al. 2010 J. Virol. 84: 5604; Bertam et al. 2010 J. Virol. 84:10016; Bertam et al. 2010 J. Virol. 84:10016; Böttcher-Friebershäusser et al. 2011 J. Virol. 85: 1554; Bahgat et al. 2011 Virol. J. 8:27).
Development of an in vivo system, e.g., a rodent model of infection, is needed in order to identify and test compounds including antibodies that specifically target human type II transmembrane serine proteases for the treatment and prevention of viral infection and other diseases.